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Assessment of vaccine efficacy on end points used in Phase IIB test-of-concept trials will require taking into consideration the effect of variables correlated with the end points and distribution of the variables within subgroups of the trial population. Here we report that evaluation of sexual activity in vaccinees and longitudinal collection of plasma viral load data from putative transmitters prior to transmission will contribute to the plausible assessment of efficacy against acquisition of infection. Data also suggest that efficacy on post-infection end points may depend on whether transmission pairs are matched or mismatched for HLA class I alleles.

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The significantly higher surface expression of the surface heat-shock protein receptor CD91 on monocytes of human immunodeficiency virus type-1 (HIV-1)-infected, long-term nonprogressors suggests that HIV-1 antigen uptake and cross-presentation mediated by CD91 may contribute to host anti-HIV-1 defenses and play a role in protection against HIV-1 infection. To investigate this further, we performed phenotypic analysis to compare CD91 surface expression on CD14(+) monocytes derived from a cohort of HIV-1-exposed seronegative (ESN) subjects, their seropositive (SP) partners, and healthy HIV-1-unexposed seronegative (USN) subjects. The median fluorescent intensity (MFI) of CD91 on CD14(+) monocytes was significantly higher in ESN compared with SP (P = 0.028) or USN (P = 0.007), as well as in SP compared with USN subjects (P = 0.018). CD91 MFI was not normalized in SP subjects on highly active antiretroviral therapy (HAART) despite sustainable, undetectable plasma viraemia. Data in three SP subjects experiencing viral rebounds following interruption of HAART showed low CD91 MFI comparable with levels in USN subjects. There was a significant positive correlation between CD91 MFI and CD8(+) T cell counts in HAART-naïve SP subjects (r = 0.7, P = 0.015). Increased surface expression of CD91 on CD14(+) monocytes is associated with the apparent HIV-1 resistance that is observed in ESN subjects.

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It is unclear how human immunodeficiency virus (HIV) type 1-specific immune responses in exposed seronegative (ESN) individuals differ from those in HIV-1-infected subjects. By use of overlapping peptides spanning Gag, Tat, Nef, Vif, Vpr, and Vpu, peripheral blood mononuclear cells from ESN individuals, their seropositive (SP) partners, and unexposed seronegative control subjects were screened for interferon- gamma production. Responses were more frequent (95.7% vs. 20%), of a higher magnitude (9-fold), and of wider breadth (median number of peptides recognized, 18 vs. 2.5) in SP than in ESN individuals. Peptides recognized by ESN individuals were less frequently recognized by their SP partners. SP subjects infrequently recognized peptides from Vif, and such responses were subdominant; among ESN individuals, this HIV-1 protein was most frequently recognized. Immunodominant peptides recognized by SP subjects tended to be from relatively conserved regions, whereas peptides recognized by ESN individuals were associated with slow disease progression.

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CD4(+) T cell help is important for the functionality of CD8(+) cytotoxic T-lymphocytes (CTLs) in limiting viral replication and may contribute to mediation of apparent resistance to HIV-1 infection in exposed seronegative (ESN) individuals. Using five HIV-1 antigens in an intracellular cytokine assay, the presence of specific antigen-responsive interferon- gamma-positive (IFN-gamma(+)) CD69(+) CD4(+) T-lymphocytes was evaluated in ESNs, their seropositive partners, and unexposed seronegative controls. Ten ESNs (five females, five uncircumcised males) were identified from 10 HIV-1 serodiscordant couples with a history of frequent unprotected sexual intercourse. All ESNs and controls were negative on two EIAs and for HIV-1 proviral DNA. The frequency of ESNs with antigen-responsive IFN-gamma(+) CD69(+) CD4(+) T-lymphocytes ranged from three to five of eight for the different HIV-1 antigens. Six of eight ESNs tested had a positive response to at least one of the five antigens. Responses were on average 3.5 times higher among seropositives compared to ESNs and absent in the five unexposed controls. A negative correlation was noted between responses in ESNs and the plasma viral load of their seropositive spouse. Clade-specific and cross-clade reactivity were noted in both ESNs and seropositive partners tested. The findings confirm that ESNs are in a state of HIV-1-specific immune activation and suggest that HIV-1-specific IFN-gamma(+) CD69(+) CD4(+) T-lymphocytes in addition to HIV-1-specific CD8(+) CTLs already described by others are potential immunological correlates of protection from persistent HIV-1 infection.

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Type-specific immunoglobulin G (IgG) to pneumococcal capsular polysaccharide (CPS) and opsonic activity against Streptococcus pneumoniae were evaluated in serum samples from 36 Ugandan adults with community-acquired pneumonia and 58 asymptomatic Ugandan adults with or without human immunodeficiency virus type 1 (HIV-1) infection. The levels of serum IgG to CPS were significantly higher in HIV-1-infected subjects than in HIV-uninfected subjects. Serum samples from HIV-1-infected subjects that had lower IgG titers demonstrated higher opsonic activity against type 3 (titers of 7) and type 9 (titers of 7-11) pneumococcal strains. Plasma HIV-1 load also correlated inversely with serum opsonic activity against these strains, and peripheral blood CD4+ lymphocyte numbers also tended to correlate with serum opsonic activity in asymptomatic HIV-1-infected adults. Our findings suggest that the opsonic activity of type-specific IgG is impaired in the serum of HIV-1-infected African adults, which may expose them to a serious risk of invasive pneumococcal infections.

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Convenient, non-food-dependent dosing, low tablet volume, and relatively low cost have made nonnucleoside reverse transcriptase inhibitors a first choice for both clinicians and patients in Uganda. Concerns exist as to their efficacy in patients with viral loads (VL) above 100,000 copies/ml, a feature common to about 75% of HIV-1-infected patients presenting at the Joint Clinical Research Center (JCRC) in Uganda. Furthermore, there are few data on the response to such therapy of non-B subtypes, A and D, predominant in Uganda. Presented here is a retrospective analysis of therapeutic responses in 11 antiretroviral (ARV) naïve HIV-1-infected Ugandan patients who had been initiated on zidovudine (AZT), lamivudine (3TC), and efavirenz (EFV). Laboratory assessments subsequent to initiation of ARV therapy, done at 11.6 +/- 3.9 weeks and 30.6 +/- 5.9 weeks, showed 88.9 and 71.4% patients achieved undetectable viral load, respectively. Virological suppression to below detection occurred in 85.7% of patients at 11.6 weeks despite baseline VL >or= 100,000 copies/ml. At 31 weeks there was a median increment of +183 cells/mm(3) in CD4(+) T lymphocytes. These findings reflect significant efficacy in the use of AZT + 3TC + EFV in advanced ARV naive non-B subtype HIV-1-infected patients. The therapeutic responses were comparable to those previously described in the western world.

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